Systems and methods for inducing electric field pulses in a body organ

ABSTRACT

Systems and methods for providing controllable pulse parameter magnetic stimulation are described. One aspect is directed to a magnetic stimulation system for inducing approximately rectangular electric field pulses in a body organ, comprising an electrical energy storage device, a stimulating coil, and a switching means for electrically coupling said electrical energy storage device to said stimulating coil to produce current pulses in said stimulating coil which generates, in response to the current pulses, magnetic field pulses that can induce approximately rectangular electric field pulses in the body organ.

CROSS REFERENCE TO RELATED CASES

The present application is a national stage entry of InternationalApplication No. PCT/US2007/012825, filed May 31, 2007, which claimspriority to, and the benefit of, U.S. patent application Ser. No.11/729,517, filed Mar. 28, 2007, and also claims priority to, and thebenefit of, U.S. Patent Application Ser. No. 60/814,277, filed Jun. 15,2006, and U.S. Patent Application Ser. No. 60/905,561, filed Mar. 7,2007, the entireties of both of which applications are herebyincorporated herein by reference.

FIELD

The disclosed subject matter relates to systems and methods forproviding controllable pulse parameter magnetic stimulation that induceselectric field pulses in a body organ.

BACKGROUND

Magnetic stimulation is a noninvasive tool for the study of the humanbrain and peripheral nerves that is being investigated as a potentialtherapeutic agent in psychiatry and neurology. When applied to thebrain, this technique is commonly referred to as Transcranial MagneticStimulation (TMS). However, the term “TMS” is often used to refer tomagnetic stimulation of other body organs as well. Therefore, the termTMS will be used hereinafter to refer to magnetic stimulation of thebrain or other body organs.

In TMS, a pulsed current sent through a coil produces a magnetic fieldthat induces an electric field in the brain, which can affect neuronalactivity. A single TMS pulse can activate a targeted brain circuit. Forexample, a TMS pulse delivered to the motor cortex can result in atwitch of the associated muscles in the body. Further, a single TMSpulse can also disrupt neural activity. For example, a TMS pulsedelivered to the occipital cortex can mask the perception of a visualstimulus. This allows researchers to probe brain circuits on amillisecond time scale.

A train of TMS pulses, referred to as repetitive TMS (rTMS), can produceexcitatory or inhibitory effects which last beyond the stimulationinterval. Repetitive TMS provides a means to study higher cognitivefunctions, and it could potentially be used as a therapeuticintervention in psychiatry and neurology.

The neural response to TMS is sensitive to the parameters of thestimulating TMS pulse. The pulse width (PW), shape (e.g., sinusoidal vs.rectangular), and the relative amplitude of the positive and negativephases (degree of bidirectionality) of the induced electric field affectthe physiological response to TMS, the power efficiency of thestimulator, and the heating of the stimulating coil. Existing TMSsystems are capable of inducing only damped cosine electric field pulseshapes, with a limited set of discrete choices of pulse width and degreeof bidirectionality. Further, in existing TMS systems, monophasicmagnetic field pulse shapes are associated with very low powerefficiency of the stimulator in rTMS applications.

SUMMARY

Systems and methods are disclosed for providing controllable pulseparameter magnetic stimulation that induces electric field pulses in abody organ.

One aspect is directed to a magnetic stimulation system for inducingapproximately rectangular electric field pulses in a body organ,comprising an electrical energy storage device, a stimulating coil, anda switching means for electrically coupling said electrical energystorage device to said stimulating coil to produce current pulses insaid stimulating coil which generates, in response to the currentpulses, magnetic field pulses that can induce approximately rectangularelectric field pulses in the body organ.

Another aspect is directed to a magnetic stimulation system for inducingapproximately rectangular electric field pulses in a body organ,comprising a first and a second electrical energy storage device, astimulating coil, a first switching means to electrically couple saidfirst electrical energy storage device to the stimulating coil toproduce current pulses with a positive rate of change in the stimulatingcoil, and a second switching means to electrically couple said secondelectrical energy storage device to said stimulating coil to producecurrent pulses with a negative rate of change in the stimulating coil,wherein the stimulating coil produces, in response to a combination ofthe current pulses with the positive and negative rates of change,magnetic field pulses that can induce approximately rectangular electricfield pulses in the body organ.

Another aspect is directed to a method of inducing approximatelyrectangular electric field pulses in a body organ with a magneticstimulation system. The method comprises providing a first and a secondenergy storage device, providing a stimulating coil, providing a firstswitching means electrically coupled to the first energy storage deviceand the stimulating coil, providing a second switching meanselectrically coupled to the second energy storage device and thestimulating coil, actuating the first switching means to electricallycouple the first energy storage device to the stimulating coil for afirst period of time to produce current pulses with a positive rate ofchange in the stimulating coil, actuating the second switching means toelectrically couple the second energy storage device to the stimulatingcoil for a second period of time to produce current pulses with anegative rate of change in the stimulating coil, and thereby causing thestimulating coil to produce, in response to a combination of the currentpulses with the positive and negative rates of change, magnetic fieldpulses that can induce approximately rectangular electric field pulsesin the body organ, and positioning the stimulating coil proximate to thebody organ and exposing the body organ to the magnetic field pulsesthereby inducing the approximately rectangular electric field pulses inthe body organ.

Another aspect is directed to a magnetic stimulation system for inducingadjustable pulse width electric field pulses in a body organ, comprisingan electrical energy storage device, a stimulating coil; and a switchingmeans for electrically coupling said electrical energy storage device tosaid stimulating coil, to produce selectively-adjustable-width currentpulses in said stimulating coil which generates, in response to thecurrent pulses, magnetic field pulses that can induceselectively-adjustable-width electric field pulses in the body organ.

Another aspect is directed to a method of inducing adjustable pulsewidth electric field pulses in a body organ. The method comprisesproviding an electrical energy storage device, providing a switchingmeans, providing a stimulating coil, and electrically coupling saidelectrical energy storage device to said stimulating coil with saidswitching means to produce selectively-adjustable-width current pulsesin said stimulating coil which generates, in response to the currentpulses, magnetic field pulses that can induceselectively-adjustable-width electric field pulses in the body organ.

Another aspect is directed to a magnetic stimulation system for inducingelectric field pulses with an adjustable degree of bidirectionality in abody organ, comprising a first and a second electrical energy storagedevice, a charging means electrically coupled to the first and secondelectrical energy storage devices for charging the first electricalenergy storage device to a selectable first voltage and charging thesecond electrical energy storage device to a selectable second voltage,a stimulating coil, a first switching means to electrically couple thefirst electrical energy storage device to the stimulating coil toproduce current pulses with a positive rate of change in the stimulatingcoil, and a second switching means to electrically couple the secondelectrical energy storage device to said stimulating coil to producecurrent pulses with a negative rate of change in the stimulating coil,wherein the stimulating coil produces, in response to a combination ofthe current pulses with the positive and negative rates of change,magnetic field pulses that can induce electric field pulses in the bodyorgan, the degree of bidirectionality being determined by the ratio ofthe selectable first voltage and the selectable second voltage.

Another aspect is directed to a method of inducing electric field pulseswith an adjustable degree of bidirectionality in a body organ. Themethod comprises providing a first and a second electrical energystorage device, providing a charging means electrically coupled to thefirst and second electrical energy storage devices for charging thefirst electrical energy storage device to a selectable first voltage andcharging the second electrical energy storage device to a selectablesecond voltage, providing a stimulating coil, providing a firstswitching means electrically coupled to the first electrical energystorage device and the stimulating coil, providing a second switchingmeans electrically coupled to the second electrical energy storagedevice and the stimulating coil, setting a desired degree ofbidirectionality by selecting respective amplitudes for the first andsecond voltages, the degree of bidirectionality being determined by theratio of the selected first voltage and the selected second voltage,actuating said first switching means to electrically couple the firstelectrical energy storage device to the stimulating coil for a firstperiod of time to produce current pulses with a positive rate of changein the stimulating coil, actuating said second switching means toelectrically couple the second electrical energy storage device to thestimulating coil for a second period of time to produce current pulseswith a negative rate of change in the stimulating coil, and therebycausing the stimulating coil to produce magnetic field pulses inresponse to a combination of the current pulses with the positive andnegative rates of change; and positioning the stimulating coil proximateto the body organ and exposing the body organ to the magnetic fieldpulses thereby inducing electric field pulses in the body organ with thedesired degree of bidirectionality.

Another aspect is directed to a magnetic stimulation system for inducingelectric field pulses in a body organ, comprising an electrical energystorage device, a stimulating coil, a switching means for electricallycoupling said electrical energy storage device to said stimulating coilto produce current pulses in said stimulating coil which generates, inresponse to the current pulses, magnetic field pulses that can induceelectric field pulses in the body organ, the electric field pulseshaving a plurality of selectively adjustable parameters from a groupconsisting of amplitude, pulse width, degree of bidirectionality andpulse frequency; and an operator-controlled apparatus including meansfor independently controlling at least two of said parameters.

Another aspect is directed to a method for inducing electric fieldpulses in a body organ with a magnetic stimulation system. The methodcomprises providing an electrical energy storage device, providing astimulating coil, electrically coupling said electrical energy storagedevice to said stimulating coil with a switching means to producecurrent pulses in said stimulating coil which generates, in response tothe current pulses, magnetic field pulses that can induce electric fieldpulses in the body organ, the electric field pulses having a pluralityof selectively adjustable parameters from a group consisting ofamplitude, pulse width, degree of bidirectionality and pulse frequency,detecting physiological effects induced in the body organ by theelectric field pulses, and controlling at least two of said parametersbased on the detected physiological effects.

Another aspect is directed to a magnetic stimulation system for inducingapproximately rectangular electric field pulses in a body organ,comprising an electrical energy storage device, a stimulating coil, anda switching circuit configured for electrically coupling said electricalenergy storage device to said stimulating coil to produce current pulsesin said stimulating coil which generates, in response to the currentpulses, magnetic field pulses that can induce approximately rectangularelectric field pulses in the body organ.

Another aspect is directed to a method for inducing approximatelyrectangular electric field pulses in a body organ, comprising storingelectrical energy in an electrical energy storage device, generatingwith a stimulating coil magnetic field pulses that can induce electricfield pulses in the body organ, and switchably electrically coupling theelectrical energy storage device to the stimulating coil to producecurrent pulses in the stimulating coil which generates, in response tothe current pulses, magnetic field pulses that can induce approximatelyrectangular electric field pulses in the body organ.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustrative component diagram of a controllable pulseparameter transcranial magnetic stimulation system, according to someembodiments of the disclosed subject matter.

FIG. 2A is an illustrative block diagram of an embodiment of the powerelectronics circuitry for the controllable pulse parameter transcranialmagnetic stimulation system of FIG. 1.

FIG. 2B is an illustrative block diagram of an embodiment of the controlcomputer electronics for the controllable pulse parameter transcranialmagnetic stimulation system of FIG. 1.

FIG. 3A is an illustrative schematic diagram of another embodiment ofthe power electronics circuitry for controllable pulse parametertranscranial magnetic stimulation circuit.

FIG. 3B is an illustrative schematic diagram of an insulated-gatebipolar transistor switch with an anti-parallel diode.

FIG. 3C is an illustrative schematic diagram of a gate turn-offthyristor with an anti-parallel diode.

FIGS. 3D-3F are illustrative schematic diagrams of snubber circuits.

FIG. 4A is an illustrative graph of a positive magnetic pulse generatedby using the controllable pulse parameter transcranial magneticstimulation circuit of FIG. 3A.

FIG. 4B is an illustrative graph of a negative magnetic pulse generatedusing the controllable pulse parameter transcranial magnetic stimulationcircuit of FIG. 3A.

FIG. 5A shows illustrative waveforms of a monophasic magnetic fieldpulse (B), an associated electric field (E), and neuronal membranevoltage (V_(m)) induced in the brain by a controllable pulse parametertranscranial magnetic stimulation system, according to one embodiment ofthe disclosed subject matter.

FIG. 5B shows illustrative waveforms of a biphasic magnetic field (B),an associated electric field (E), and neuronal membrane voltage (V_(m))induced in the brain by a controllable pulse parameter transcranialmagnetic stimulation system, according to one embodiment of thedisclosed subject matter.

FIG. 6 is an illustrative waveform depicting user-adjustable pulseparameters, according to one embodiment of the disclosed subject matter.

FIG. 7 shows illustrative waveforms of approximately rectangular inducedelectric field pulses with pulse widths adjustable over a continuousrange of values, generated by a controllable pulse parametertranscranial magnetic stimulation circuit, according to one embodimentof the disclosed subject matter.

FIG. 8 shows illustrative waveforms of approximately rectangular inducedelectric field pulses with bidirectionality adjustable over a continuousrange, generated by a controllable pulse parameter transcranial magneticstimulation circuit, according to one embodiment of the disclosedsubject matter.

FIG. 9 is an illustrative waveform of repetitive TMS with predominantlyunipolar induced electric field pulses, with adjustable pulse repetitionfrequency, according to one embodiment of the disclosed subject matter.

FIG. 10 is an illustrative simulation circuit for producing controllablepulse parameter transcranial magnetic stimulation, in accordance withthe disclosed subject matter.

FIG. 11 is a table of pulse performance metrics used to evaluate theefficiency of controllable pulse parameter transcranial magneticstimulation pulses.

FIG. 12A shows an illustrative waveform of a stimulated coil currentproduced by the simulation circuit of FIG. 10.

FIG. 12B shows an illustrative waveform of a stimulated peak inducedelectric field produced by the simulation circuit of FIG. 10.

FIG. 12C shows an illustrative waveform of a stimulated estimatedneuronal membrane voltage change produced by the simulation circuit ofFIG. 10.

FIG. 13A is an illustrative block diagram of power electronics circuitryfor a controllable pulse parameter transcranial magnetic stimulationsystem, according to another embodiment of the disclosed subject matter.

FIG. 13B is an illustrative block diagram of another embodiment of thecontrol computer electronics for the controllable pulse parametertranscranial magnetic stimulation system.

FIG. 14 is an illustrative schematic of a controllable pulse parametertranscranial magnetic stimulation circuit, according to anotherembodiment of the invention.

FIG. 15A shows illustrative waveforms of voltage across capacitor C₅ fordifferent pulse widths of the controllable pulse parameter transcranialmagnetic stimulation circuit of FIG. 14.

FIG. 15B shows illustrative waveforms of voltage induced in the coil Lfor different pulse widths of the controllable pulse parametertranscranial magnetic stimulation circuit of FIG. 14.

FIG. 15C shows illustrative waveforms of estimated neuronal membranevoltage change for different pulse widths induced with the controllablepulse parameter transcranial magnetic stimulation circuit of FIG. 14.

DETAILED DESCRIPTION

The disclosed subject matter provides, among other things, acontrollable pulse parameter transcranial magnetic stimulation (cTMS)system that induces approximately rectangular electric field pulses inan organ of a body, such as a human brain for example. The amplitude,pulse width, and degree of bidirectionality of the induced electricfield pulses are adjustable over a continuous range of values. Thedegree of bidirectionality is defined as the ratio of the positive phaseamplitude to the negative phase amplitude of the induced electric fieldpulse. By adjusting the degree of bidirectionality, the induced electricfield pulse can be varied from bipolar (i.e., equal amplitudes of thepositive and negative phases) to predominantly unipolar (i.e., a largeamplitude of one phase for one polarity and a small amplitude of theother phase for the opposite polarity).

In some embodiments, the cTMS system disclosed herein switches astimulating coil between positive-voltage and negative-voltage energystorage capacitors or capacitor banks using high-power semiconductordevices. Controlling the pulse parameters facilitates enhancement of TMSas a probe of brain function and as a potential therapeuticintervention. Independent control over the pulse parameters (e.g., pulsewidth, pulse amplitude, degree of bidirectionality) facilitates definingdose-response relationships for neuronal populations and producingclinical and physiological effects. For example, dose-responserelationships for specific neuronal populations can be defined, andselected clinical and physiological effects can be enhanced. Moreover,the cTMS system disclosed herein also enables high-frequency (≧1 Hz)repetitive TMS (rTMS) with predominantly unipolar induced electricfields.

Referring to FIG. 1, in one embodiment, an illustrative componentdiagram of a controllable pulse parameter transcranial magneticstimulation system 100 is shown. The cTMS system 100 includes a powerelectronics housing 120, a positioning arm 130, a stimulating coil L,and a digital data processing device, such as control computerelectronics 110. The control computer electronics 110 includes a controlcomputer electronics housing 102 with a digital data processing deviceand a storage device (e.g., a hard disk), a keyboard 104, a monitor 106,and a mouse 105 (or trackball), and/or other data entry devices. Thepower electronics circuitry in housing 120 includes cTMS system powerelectronics that supply current to the stimulating coil L, which can bepositioned and held proximate to a patient's head by the positioning arm130. The power electronics circuitry in the power electronics housing120 is controlled by the control computer electronics 110. An operator,operating the control computer electronics 110, controls the powerelectronics in power electronics housing 120 to produce one or moreadjustable current pulses that are passed through the stimulating coil Lheld by positioning arm 130. During a medical treatment, the stimulatingcoil L is positioned proximate to a patient's head. The adjustablecurrent pulses that are passed through the stimulating coil L result inthe stimulating coil L generating adjustable magnetic field pulses,which induce adjustable electric field pulses which, in turn, induceadjustable current pulses in the patient's brain.

Referring to FIGS. 2A and 2B, illustrative block diagrams of embodimentsof the power electronics circuitry in housing 120 and the controlcomputer electronics in housing 102 are respectively shown. The powerelectronics housing 120 houses electronics used to drive the stimulatingcoil L. The electronics in the housing 120 include a charger 210, afirst capacitor C1, a second capacitor C2, a first capacitor discharger215, a second capacitor discharger 216, a first semiconductor switch Q1,a second semiconductor switch Q2, a first snubber circuit 222, a secondsnubber circuit 223, a third snubber circuit 224, a fourth snubbercircuit 225, a fifth snubber circuit 226, a first gate drive 220, and asecond gate drive 221.

The control computer housing 102 houses a typical central processingunit (CPU) (not shown), and various standard printed circuit board slots(not shown). Inserted into one of the slots is a controller board 205that provides control signals used to control the cTMS system 100, andis discussed in further detail below.

In one embodiment, capacitor C1 and capacitor C2 are single capacitors.In another embodiment, capacitor C1 and capacitor C2 each represent aseparate bank of capacitors. The capacitors in each separate bank areconnected in parallel and/or in series with each other.

Referring to FIG. 3A, an illustrative schematic diagram of thecontrollable pulse parameter transcranial magnetic stimulation circuitfor driving the stimulation coil L is shown. As previously described inconnection with the block diagram of FIGS. 2A and 2B, the controllablepulse parameter transcranial magnetic stimulation circuit for drivingthe stimulation coil L includes energy storage capacitor (or bank ofcapacitors) C1, energy storage capacitor (or bank of capacitors) C2,controllable semiconductor switch Q1, controllable semiconductor switchQ2, the first and second gate drives 220, 221, and charger 210. Thecircuit of FIG. 3A additionally includes a diode D1 connected inanti-parallel with the controllable semiconductor switch Q1, and a diodeD2 connected in anti-parallel with the controllable semiconductor switchQ2.

Referring again to FIGS. 2A, 2B, and 3A, in one embodiment, an operatorcontrols the cTMS system using the control computer electronics 110. Theoperator selects cTMS system operation with monophasic or biphasicmagnetic pulses and a desired set of induced electric field pulseparameters such as pulse amplitude (A), width of positive pulse phase(PW⁺), width of initial negative pulse phase (PW⁻ can be chosen for thebiphasic pulse only), ratio of negative to positive capacitor voltage(M), which determines the degree of bidirectionality, and the frequencyof pulse repetition (f_(train)) via a graphical user interface(discussed below) executing on the control computer 102. The selectedvalues are stored in the control computer 102.

The controller board 205 is in communication with and controls thecharger 210, the first gate drive 220, the second gate drive 221, andcapacitor discharger 215 (which includes resistor 340 and normallyclosed relay 342) and capacitor discharger 216 (which includes resistor344 and normally closed relay 346) via connections 273, 275, 276, 277,and 278, respectively. The controller board 205 is also in communicationwith, and receives data from, the energy storage capacitors C1 and C2,and the stimulating coil L via connections 272, 271, 274, respectively.

The charger 210 charges the energy storage capacitor C1 to a positivevoltage V_(C1) (set by the operator), and the energy storage capacitorC2 is charged to a negative voltage −V_(C2) (set by the operator). Thecharger transfers energy from a power line to the capacitors, andtransfers energy between the two capacitors. The positive and negativecapacitor voltages are independently selectable. Voltage V_(C1) is setbased on the pulse amplitude (A) selected by the operator, and voltageV_(C2) is set equal to M*V_(C1), where M is the ratio of negative topositive capacitor voltage selected by the operator. The stimulatingcoil L is connected to capacitors C1 and C2 via the semiconductorswitches Q1 and Q2, and diodes D1 and D2, respectively.

The controller board 205 also supplies separate sets of timing pulseswith adjustable widths (set by the operator) to the first and secondgate drives 220, 221. The first and second gate drives 220, 221 each usethe timing pulses to produce separate sets of voltage pulses withadjustable widths.

In FIG. 3A, each semiconductor switch Q1 and Q2 includes a gate terminal305 and 310, respectively. The gate terminals 305 and 310 are driven(i.e., clocked) by the voltage pulses supplied by the gate drives 220and 221. The voltage pulses from controller board 205 are used to switchthe semiconductor switches Q1 and Q2 to an on state or an off state.Anti-parallel connected diodes D1 and D2 transfer energy from thestimulating coil L back to capacitors C1 and C2, respectively.

The semiconductor switch Q1 connects coil L to energy storage capacitorC1 for an interval of time equal to the pulse width of the voltagepulses received at the gate terminal 305 from the first gate drive 220,which causes the coil current I_(L) to increase during this interval oftime. When semiconductor switch Q1 is turned off, the coil currentcommutates to capacitor C2 through diode D2, and the coil current startsto decrease until it reaches zero. Thus, turning switch Q1 on and offresults in an approximately triangular positive coil current pulse,which induces an approximately triangular positive monophasic magneticfield pulse. This is discussed in further detail with respect to FIG.4A. Likewise, the semiconductor switch Q2 connects coil L to energystorage capacitor C2 for an interval of time equal to the pulse width ofthe voltage pulses received at the gate terminal 310 from the secondgate drive 221, which causes the coil current I_(L) to decrease (i.e.,become more negative) during this interval of time. When semiconductorswitch Q2 is turned off, the coil current commutates to capacitor C1through diode D1, and the coil current starts to increase (i.e., becomemore positive) until it reaches zero. Thus, turning switch Q2 on and offresults in an approximately triangular negative coil current pulse,which produces an approximately triangular negative monophasic magneticfield pulse. This is discussed in further detail with respect to FIG.4B. If an adjustable negative monophasic magnetic field pulse and anadjustable positive monophasic magnetic field pulse are both generatedsubsequently, an adjustable biphasic magnetic pulse is produced. Theapproximately triangular magnetic field pulses with adjustable widthsinduce approximately rectangular electric field pulses in an organ of abody. The approximately rectangular electric field pulses, in turn,induce approximately rectangular, adjustable-pulse-parameter currentpulses in an organ of a body, such as a human brain, for example.

The controller board 205 provides timing signals with microsecondresolution to control the semiconductor switches. The cTMS system usestiming of the turn-on and turn-off transitions of the control signalsfor both semiconductor switches Q1 and Q2 to provide accurate pulsewaveform control.

In one embodiment, the controller board 205 is a PCI card from NationalInstruments (Austin, Tex.) with additional interface electronics thatprovides sub-microsecond timing signals. Additional interfaceelectronics includes signal conditioning and isolation circuits such asoptocouplers, fiber optic links, isolation transformers, attenuators,amplifiers, and filters, as required to connect the controller board 205to the power electronics in the power electronics housing 120. The PCIcard (controller board 205) resides in the control computer housing 102that provides a GUI for interfacing and configuring the controller board205. The control computer housing 102 also houses a mass storage device,such as a hard disk (not shown) for storing data. The GUI is implementedin LabVIEW software (available from National Instruments Corp.). Theoperator inputs various pulse parameters, which are discussed in detailbelow. The controller board software computes the correspondingcapacitor voltages (V_(C1), V_(C2)) and switch timing. The controllerboard 205 then sends the capacitor voltage commands to the charger 210,capacitor dischargers 215, 216, and the switch timing signals to thegate drives 220, 221. The controller board 205 also samples V_(C1),V_(C2)) and I_(L), (via connections 271, 272, 274) to monitor circuitoperation, and inhibits or prevents coil currents from exceedingspecifications.

Typically, the controllable semiconductor switches Q1 and Q2 should beable to withstand the peak coil current and the peak voltages appearingacross their terminals at the peak pulse repetition frequency. Theswitches Q1 and Q2 should also have turn-on and turn-off times of nomore than a few microseconds. The maximum voltage of the semiconductorswitches Q1 and Q2 is ideally V_(C1)+V_(C2). However, during currentcommutation between the two energy storage capacitors C1 and C2, theswitch voltage can overshoot this value due to stray inductance and thefinite turn-off and turn-on times of the semiconductor switches Q1 andQ2, and diodes D1 and D2. To address this issue, semiconductor deviceswith fast switching times should be used.

In one embodiment, insulated gate bipolar transistors (IGBTs—shown inFIG. 3B and available from Powerex of Youngwood, Pa.) are used for theswitches Q1 and Q2. In another embodiment, gate-turn-off thyristors(GTOs), such as integrated gate-commutated thyristors (IGCTs) (shown inFIG. 3C) are used for switches Q1 and Q2. Both of these devices cansustain pulse currents of thousands of amperes at voltages of a fewkilovolts while turning on and off in a few microseconds. Since thesedevices can turn off while the coil current is not zero, they are usedwith the snubber circuits 222, 223, 224, 225, 226 (discussed in detailbelow) which absorb the energy of the commutation transients, thusinhibiting and/or preventing voltage overshoots that exceed the voltageratings of the semiconductor switches, and energy dissipation in thesemiconductor switches, which occurs during switching.

Unlike the silicon-controlled rectifiers (SCRs) used in conventionalstimulators, IGBTs can be both turned on and off from the gate terminal.There are existing IGBT modules with peak voltage/surge current ratingsof 3300 Volts/12000 Amperes, 4500 Volts/6000 Amperes, 4500 Volts/9000Amperes, and 6500 Volts/6000 Amperes, and switching times of about onemicrosecond, which can be used to implement a cTMS system. These IGBTmodules have an integrated ultra-fast reverse diode between the emitterand the collector (e.g., D1 and D2 in FIG. 3), which clamps the IGBTreverse voltage, and provides a free-wheeling path for the coil currentI_(L).

IGCTs behave like efficient SCRs when turning on and during conduction,and behave like IGBTs when turning off. The turn-on time for an IGCT isapproximately 1 μs, but the turn-off time can be as long as 10 μs. IGCTswith integrated reverse diodes (e.g., D1 and D2) and gate drives (e.g.,gate drive 220, 221) are available with ratings of 4500 Volts and 17000Amperes surge current, providing for robustness of the design.

In the cTMS system, the stimulating coil L is forced to commutatebetween the two energy storage capacitors C1 and C2 when the coilcurrent is at its peak. Managing the forced commutation transient is achallenging aspect of implementing the cTMS system. The finite turn-offand turn-on times of the semiconductor switches Q1 and Q2, and the strayinductance in the capacitor banks C1 and C2, the switches Q1 and Q2, thediodes D1 and D2, and the wiring between them, can result in voltageovershoots that exceed the voltage ratings of the semiconductorswitches, and switching power loss and heating in the semiconductorswitches. The stray inductances are reduced and/or minimized byinstalling the semiconductor switches Q1 and Q2, the diodes D1 and D2,and the capacitor banks C1 and C2 as close together as allowed by thephysical dimensions of the components, and interconnecting them withwires or bus bars arranged to minimize the area of the current loop.Still, stray inductance cannot be completely eliminated. For example, atypical capacitor bank series inductance of 150 nH with 7 kA currentstores magnetic energy sufficient to produce a 27 kV spike on an IGBTswitch with 10 nF collector capacitance, which would exceed the voltagerating of a 4500 V IGBT by 22500 V, resulting in potential damage to theIGBT. Therefore, the snubber circuits 222, 223, 224, 225, 226 are usedto slow down the transients, ameliorate power dissipation in thesemiconductor switches Q1 and Q2, and provide paths for strayinductances to discharge in order to suppress the voltage overshoots.

In one embodiment, as shown in FIG. 3A, the snubber circuits 222, 223each include a capacitor 312, 318 in series with a diode 314, 320 andresistor 316, 322, which are in parallel with each other. Snubbercircuits 222, 223 each also include capacitors 326, 330. Thisconfiguration allows the stimulating coil current to flow through thesnubber capacitor 312, 318 when the corresponding semiconductor switchQ1, Q2 is turning off, thus inhibiting and/or preventing voltageovershoots. The snubber capacitor 312, 318 should be large enough tohold the peak switch voltage below its rated limit. If the snubbercapacitor 312, 318 is too large, switching losses are increased. Snubbercircuit 224 includes capacitor 324, snubber circuit 225 includescapacitor 328, and snubber circuit 226 includes capacitor 332 andresistor 334.

Snubber circuits 222 and 223 (see FIGS. 2A, 3A) can include the circuitembodiments shown in FIGS. 3D, 3E and/or 3F. Snubber circuits 224, 225,and 226 (see FIG. 2A) can include the circuit embodiments shown in FIGS.3D and/or 3E.

Approaches for sizing of snubber components will be readily understoodby those of ordinary skill in the art, and include, but are not limitedto, approaches discussed in manufacturer application notes.

The gate drives 220, 221 serve to drive (clock) the semiconductorswitches Q1 and Q2 to an on state or an off state. As previouslydiscussed, the gate drives 220, 221 receive timing signals from thecontroller board 205, and apply gate voltages to the gates 305, 310.Some high-power switches, such a IGCTs, are manufactured with anintegrated gate drive unit. IGBTs require a separate external gatedrive. For high-power IGBTs, 10-20 μC is delivered to the gate to raisethe gate-emitter voltage to 15-20 Volts to turn on the device. To switchthe gate in about 1 μs, IGBT gate drives need an output impedance of afew ohms, and provide peak currents of a few Amperes. IGBT gate drivesare available commercially. In some implementations, the gate drives220, 221 incorporate short-circuit protection which prevents the switchfrom turning on if a short circuit is detected between the collector andemitter terminals (in IGBTs) or the anode and cathode terminals (in GTOsand IGCTs), which improves the fault tolerance and safety of the cTMSsystem.

The pulse width control parameters, PW⁺ and PW⁻ are limited by thedischarge of C1 and C2, respectively. To enable pulse width control overa significant range (e.g., up to hundreds of microseconds) and toproduce approximately rectangular induced electric field pulses, theenergy storage capacitors C1 and C2, in most embodiments disclosedherein, have capacitances in the range of 300 to 800 μF, and 1000 to3000 μF, respectively. These capacitance values can be accomplished withsingle pulse capacitors or with banks of parallel and/or seriesconnected pulse capacitors. Suitable capacitor technologies forimplementation of C1 and C2 use oil, polypropylene, and/or polyesterdielectrics. For example, in one embodiment, C1 is implemented using twoparallel 185 μF, 3 kV oil-filled pulse capacitors (e.g., General Atomicsmodel 39504), and C2 is implemented using two parallel 750 μF, 1 kVoil-filled pulse capacitors (e.g., General Atomics model 310DM475). Themaximum C1 voltage V_(C1) is 2,800 V, and the minimum (maximum negative)C2 voltage—V_(C2) is 900 V.

Whereas in conventional TMS systems the voltage on the energy storagecapacitor is reversed during the pulse, in the disclosed cTMS system thevoltages on the capacitors C1 and C2 are never reversed, i.e., alwaysV_(C1)≧0 and −V_(C2)≦0. Capacitor voltage reversal decreases thecapacitor life expectancy by as much as ten times. Therefore, theenergy-storage capacitors C1 and C2 of the disclosed cTMS system have alonger life expectancy since no capacitor voltage reversal occurs.

The capacitor charger 210 for the cTMS system supplies energy to boththe capacitors C1 and C2 at two independently controlled DC voltages,V_(C1) and V_(C2), respectively. The capacitor charger 210 alsotransfers energy from capacitor C2 to capacitor C1 to recover energyaccumulated on capacitor C2 after a monophasic positive current pulse incoil L, corresponding to a positive monophasic magnetic field pulse. Thecapacitor charger 210 also transfers energy from capacitor C1 tocapacitor C2 to recover energy accumulated on capacitor C1 after amonophasic negative current pulse in coil L, corresponding to a negativemonophasic magnetic field pulse. In one embodiment, a charging unit suchas the Magstim Super Charger (available from The Magstim Corp.,Whitland, UK) is used to charge the positive capacitor C1. Abidirectional inverting DC/DC power supply is used to transfer energybetween capacitor C1 and capacitor C2 so that V_(C2) is maintained at aset level. Capacitor dischargers 215, 216, which constitute a resistorand a normally closed relay connected in series, are included andactivated when the energy stored in capacitors C1 and C2 has to bereduced, such as when the pulse amplitude setting A is decreased by theoperator, or when the energy stored in capacitors C1 and C2 has to becompletely dissipated, such as when the cTMS system is shutdown, poweris lost, or a system fault is detected by the controller.

A stimulating coil L known in the art is used with the cTMS system. Bothair core and ferromagnetic core coils can be used with the cTMS system.A coil connector compatible with Magstim 200 coils is used to connectthe stimulating coil L to the cTMS circuitry. In one embodiment, aMagstim 16.4 μH 70 mm double stimulating coil (commonly referred to inthe art as a figure-of-8) is used.

Due to the rate of change and peak strength of the magnetic fieldrequired to achieve transcranial cortical stimulation, TMS systemsoperate at very high capacitor voltages (up to 3 kV) and peak coilcurrents (up to 10 kA). In one embodiment, the cTMS system employsmaximum positive and negative capacitor voltages of 2800 Volts and −900Volts, respectively, and a peak coil current of 7 kA.

The currents, voltages, and pulse widths applied to the energy storagecapacitors C1 and C2, stimulating coil L, coil cable and connector, andinternal wiring in the cTMS system typically do not exceed the currents,voltages, and pulse widths in conventional TMS systems. The cTMS systempower consumption in rTMS operation typically does not exceed that ofexisting TMS systems, since commensurate pulse energies and pulse trainfrequencies are used. Further, given the higher electrical efficiency oftriangular magnetic pulses, the peak values of the pulse parameterscould be reduced in comparison with available stimulators. Thus,existing solutions for these system components can be used in the cTMSsystem.

An analysis of the cTMS circuit shown in FIG. 3A will now be presentedin connection with FIGS. 4A, 4B. For this analysis, it is assumed thatstorage capacitors C1 and C2 are large. Specifically, it is assumed thatthe following conditions are met:t _(rise)<<π/2*(inductance of coil L*capacitance of capacitor C1)^(1/2)andt _(fall)<<π/2*(inductance of coil L*capacitance of capacitor C2)^(1/2),where t_(rise) and t_(fall) are the rise and fall times of the magneticfield generated by the stimulating coil L. Further, in this analysis,the component parasitics and losses in the circuit are ignored. Underthese conditions, the cTMS system induces approximately rectangularcurrent pulses in the targeted body organ.

Referring to FIGS. 4A and 4B, in one embodiment, under the conditionsspecified above, graphs of positive and negative monophasic magneticfield pulses generated using the controllable pulse parametertranscranial magnetic stimulation circuit are shown. For thisillustration, the ratio of the voltage across the capacitor C1 to thevoltage across the capacitor C2 (V_(C1):V_(C2)) is assumed to be 5:1.FIG. 4A depicts the generation of a positive magnetic field pulse 405,which is proportional to the current in the coil L.

When switch Q1 is switched to an on state 410, the resulting current(I_(L)) in the stimulating coil L increases at a rate ofdI_(L)/dt=V_(C1)/(inductance of coil L), as shown by waveform 416 inplot 415. Since capacitor C1 is very large, V_(C1) stays approximatelyconstant. After rise time t_(rise), which is set by the operator bychoosing when to turn Q1 on and off, switch Q1 is switched to an offstate forcing the current I_(L) in the stimulating coil L to commutateto capacitor C2 via the diode D2. While diode D2 is on, switch Q2 can beeither on or off (referred to as a “don't care state” of the switch, andindicated with “x” symbols in the switch state waveforms). Since anegative voltage −V_(C2) is now applied across the stimulating coil L,the stimulating coil current I_(L) starts to decrease at a rate of−V_(C2)/(inductance of coil L) as shown by waveform 417 in plot 415. Thecoil current I_(L) decays to zero in fall time t_(fall), where trail:t_(rise)=V_(C1):V_(C2). Under ideal conditions, all the energytransferred from capacitor C1 to the stimulating coil L, which is equalto (inductance of coil L)*I_(Lpk) ²/2, is returned to capacitor C2,where I_(Lpk) is the peak current in the coil L. Of course, as will beunderstood by those of ordinary skill in the art, losses will ariseunder ordinary (i.e., non-ideal) conditions, resulting in somewhat lessthan this amount of energy being transferred. This energy can betransferred back to capacitor C1 and reused in a subsequent pulse, whichmakes this strategy effective for repetitive TMS (rTMS).

FIG. 4B depicts the generation of a negative magnetic field pulse, whichis proportional to the current in the coil L as previously described.When switch Q2 is switched to an on state 425, the resulting current(I_(L)) in the stimulating coil L decreases at a rate ofdI_(L)/dt=−V_(C2)/(inductance of coil L), as shown by waveform 429 inplot 430. After rise time t_(rise), which is chosen by the operator,switch Q2 is switched to an off state forcing the current I_(L) in thestimulating coil L to commutate to capacitor C1 via the diode D1. Whilediode D1 is on, switch Q1 can be either on or off (referred to as a“don't care state” of the switch, and indicated with “x” symbols in theswitch state waveforms). Since a positive voltage V_(C1) is now appliedacross the stimulating coil L, the stimulating coil current I_(L) startsto increase at a rate of V_(C1)/(inductance of coil L) as shown bywaveform 428 in plot 430.

When the cTMS system is operated in monophasic magnetic pulse mode, asshown in FIG. 5A, the energy exchange between the storage capacitors C1and C2 is implemented using charger circuit 210 to transfer energy fromcapacitor C2 to C1, or from capacitor C1 to C2 between pulses. When thecTMS system is operated in biphasic magnetic pulse mode, as shown inFIG. 5B, the energy exchange between the storage capacitors C1 and C2 isimplemented by having a negative magnetic pulse precede a positivemagnetic pulse. The energy from the storage capacitor C1 at thebeginning of the pulse is returned to the storage capacitor C1 by theend of the pulse. The capability to operate in both monophasic andbiphasic magnetic pulse modes enables optimization of the pulse type forspecific research and clinical applications of the cTMS system.

Referring to FIG. 5A, in one embodiment, illustrative monophasicwaveforms of a magnetic field pulse (B) 505, an electric field (E) 510,and a neuronal membrane voltage (V_(m)) 515, induced in the brain by thecontrollable pulse parameter transcranial magnetic stimulation systemare shown.

As previously described, during a medical treatment, the stimulatingcoil L is positioned proximate to a patient's head. Adjustable currentpulses are passed through the stimulating coil L and cause thestimulating coil L to generate adjustable magnetic field pulses. Theadjustable magnetic field pulses induce adjustable electric field pulseswhich, in turn, induce adjustable current pulses in the patient's brain.The induced adjustable current pulses in the patient's brain result involtage change on the neuronal membrane that can be measured.

The waveforms shown in FIG. 5A are produced by the current I_(L) (plot405) in the stimulating coil L shown in FIG. 4A. As previouslydescribed, the magnetic field B (plot 505) is proportional to thecurrent I_(L) in the stimulating coil L, and thus also has a triangularshape. The induced electric field E (plot 510) is proportional to themagnetic field rate of change (dB/dt), and correspondingly has arectangular shape, rather than the cosine shape of existing TMS systems.Different rising and falling slopes of the magnetic field B (plot 505)result in different magnitudes of the positive and negative phases ofthe induced electric field E (plot 510), respectively. As previouslydescribed, the rate of change of the coil current (dI_(L)/dt) and,therefore, the rate of change of the magnetic field (dB/dt) isproportional to the voltage across the coil L. The voltage across thecoil L is equal to the voltage of the capacitor to which the coil isconnected. Therefore, the ratio of peak positive to negative electricfield E is V_(C1):V_(C2). This is true in general, even when the circuitnon-idealities are considered. Since the induced electric field pulsehas a rectangular shape, and due to the neuronal membrane capacitance,the neuronal membrane voltage (V_(m)) follows a decaying exponentialcurve characterized by the membrane time constant, as shown by plot 515.If the neuronal membrane is depolarized (i.e., made more positive) bymore than approximately 15 mV relative to its resting potential (−60 to−70 mV), the neuron is likely to produce an action potential (i.e., tofire).

Referring to FIG. 5B, in one embodiment, illustrative waveforms of abiphasic magnetic field (B) 520, and the associated electric field (E)525 and neuronal membrane voltage (V_(m)) 530 induced in the brain bythe controllable pulse parameter transcranial magnetic stimulationsystem are shown. Although the magnetic field B of plot 520 is biphasicwith symmetric positive and negative phases, the induced electric field(plot 525) has a large positive amplitude and a comparatively smallnegative amplitude, since the rate of change of the rising magneticfield is much larger than the rate of change of the falling magneticfield. As a result (plot 530), the depolarization amplitude (as theneuronal membrane is made more positive) is larger than thehyperpolarization amplitude (as the neuronal membrane is made morenegative). This example demonstrates how the cTMS system can producepredominantly unipolar electric field pulses and neuronal membranevoltage changes with biphasic magnetic pulses. In contrast, conventionalsinusoidal biphasic magnetic pulses induce electric fields and neuronalmembrane voltage changes that are bipolar (i.e., have approximatelyequal amplitudes of the positive and negative phases of the electricpulse). Biphasic magnetic pulses are more electrically efficient andproduce less coil heating than monophasic magnetic pulses. Further, TMSbiphasic magnetic pulses can be used inside a magnetic resonance imaging(MRI) scanner, since the torque on the wire loops of the stimulatingcoil L in the strong magnetic field of the scanner averages toapproximately zero. In contrast, monophasic pulses cannot be used in anMRI scanner, since the average toque on the coil loops is non-zero,resulting in high mechanical stress in the coil that can damage thecoil.

Referring to FIG. 6, in one embodiment, an illustrative waveformdepicting user-adjustable pulse parameters is shown. The user-adjustableparameters include: induced positive electric field amplitude (A) 602(which corresponds to the intensity setting on conventional TMSsystems), the pulse width of the positive phase (PW⁺) 608, the inducednegative electric field amplitude (M*A=(V_(C2)/V_(C1))*A) 604, which isspecified through M, the ratio of negative to positive capacitorvoltage, and the frequency of the pulse repetition (f_(train)). Forbiphasic operation, the duration of an initial negative electric fieldphase (PW⁻) 606 can also be specified (PW⁻=PW⁺/2M for symmetric negativeside lobes of the pulse).

Referring to FIG. 7, in one embodiment, illustrative waveforms ofapproximately rectangular, predominantly unipolar current pulses withadjustable pulse width are shown. Control over the pulse width (PW⁺) ofthe induced electric field pulse is accomplished by controlling the onand off timing of the semiconductor switches Q1 and Q2.

Referring to FIG. 8, in one embodiment, illustrative waveforms depictinguser-adjustable degree of bidirectionality of approximately rectangularelectric field pulses are shown. Control over the degree ofbidirectionality is accomplished by adjustment of the voltages of energystorage capacitors C1 and C2 relative to each other.

FIG. 9 shows an illustrative waveform of rTMS with a predominantlyunipolar induced electric field. Computer simulations of arepresentative implementation of the cTMS system (FIG. 10) indicate thatthe cTMS pulses can induce membrane depolarization and hyperpolarizationequal to that of commercial monophasic stimulators at only 16-18% of thepower dissipation. This results in a reduction of power supply demands,heating, noise, and component size, and enables the cTMS system toproduce high-frequency rTMS with predominately unipolar induced electricfields.

The cTMS system described in the disclosed subject matter was simulatedand compared to existing TMS systems. A schematic of the cTMS simulationcircuit is shown in FIG. 10. Further, a set of pulse performancemetrics, i.e. performance figures, used to evaluate the efficiency ofcTMS pulses compared to conventional pulse configurations of commercialTMS systems is shown in FIG. 11. The values were derived from computersimulations using PSIM circuit simulation software (available fromPowersim Inc.) and the simulation circuit shown in FIG. 10.

Realistic component values are used. As previously described, snubbercircuits 1001 and 1002 are added across the semiconductor devices Q1 andQ2, snubber capacitors C1 a and C1 b are added across the capacitor bankC1, and snubber capacitors C2 a and C2 b are added across capacitor bankC2 to handle transient energy.

Waveforms showing the coil current I(L), peak induced electric field(E), and estimated neuronal membrane voltage change (dV_m) correspondingto the cTMS configuration shown in FIG. 10 are shown in FIGS. 12A, 12B,and 12C, respectively.

To allow a valid comparison of the pulse shape efficiency, allconfigurations use a model of Magstim “figure-of-8”, air-core coil(L=16.4 μH), parasitic series resistance and inductance of 25 mΩ and 0.6μH, and neuronal membrane time constant τ_(m)=150 μs. The actualNeuronetics 2100 and Medtronic MagPro X100 systems use different coilsthan the Magstim figure-of-8 used in the comparison. Therefore, for thecalculations for these systems, the capacitance was adjusted to matchtheir typical pulse periods of approximately 200 and 270 μs,respectively, for the given 16.4 pH coil, because the objective is tocompare the waveform efficiency rather than the actual commercialsystems and coils.

To account for the higher efficiency of ferromagnetic (iron) core coils,standard with the Neuronetics 2100 machine, the total energy loss perpulse and the load integral (proportional to coil heating) arerecalculated for an iron core coil, as indicated in FIG. 11. The ironcore proportionally increases the efficiency of all pulseconfigurations, and can be used with the cTMS system to improveefficiency. Four representative cTMS pulse configurations are simulated(see columns cTMS¹-cTMS⁴ of FIG. 11). For biphasic cTMS pulses(cTMS²-cTMS⁴), the duration of the initial negative phase was set toPW⁻=PW⁺/2M. The amplitude of the commercial device (Magstim, MagPro,Neuronetics) pulses is adjusted to produce equal neuronal membranedepolarization of ΔV_(m)=18 mV, which is 20% above the assumed neuronalfiring threshold of 15 mV depolarization. The amplitude and pulse widthof the cTMS pulse configuration are also adjusted to produce identicalneuronal membrane depolarization of ΔV_(m)=18 mV.

FIG. 11 shows that the cTMS system can produce predominantly unipolarneuronal membrane potential change with both monophasic (cTMS¹) andbiphasic (cTMS²-cTMS⁴) magnetic field pulses. For example, the cTMS²pulse configuration yields a membrane hyperpolarization/depolarizationratio of 0.27, which is comparable to that of the Magstim 200 and MagProX100 (monophasic mode), while dissipating only 16% and 18% of theenergy, respectively. The energy dissipation per pulse was calculatedusing the following equation:

${{\Delta\; W_{C}} = {( {{1/2}{\sum\limits_{\substack{{sum}\mspace{14mu}{of}\mspace{14mu}{all} \\ {capacitors} \\ {before}\mspace{14mu}{pulse}}}{{Ci}( V_{Ci} )}^{2}}} ) - ( {{1/2}{\sum\limits_{\substack{{sum}\mspace{14mu}{of}\mspace{14mu}{all} \\ {capacitors} \\ {after}\mspace{14mu}{pulse}}}{{Ci}( V_{Ci} )}^{2}}} )}},$where Ci refers to all capacitors in the stimulator power electronics,and where capacitor Ci has voltage V_(Ci).

Further, coil heating (proportional to the load integral I_(L) ²dt) withthe cTMS² pulse is only 32% and 36% that of the Magstim 200 and MagProX100, respectively cTMS is able to achieve a total energy dissipationΔW_(C) comparable to efficient biphasic systems, such as the Neuronetics2100, with 8-59% less coil heating (load integral) while adding thepreviously unavailable functionalities of control over the inducedelectric field pulse width, degree of bidirectionality, approximatelyrectangular shape, and predominantly unipolar electric field pulses. Itshould be noted that for very brief, high-intensity rectangular pulses(cTMS⁴), the coil heating decreases dramatically, while the total energydissipation increases slightly. This is due to energy loss in the cTMSsnubber circuits, which is proportional to the square of the capacitorvoltage. However, since it is easier to cool the snubber circuits, whichare inside the power electronics enclosure, than the coil, the reducedcoil heating of brief, rectangular, high-voltage pulses can beadvantageous in high-power applications such as magnetic seizure therapy(MST) where coil heating is currently the bottleneck for pulse trainduration. Finally, in this model we have not accounted for ferromagneticcore losses, which could be higher for briefer pulses.

When monophasic magnetic field pulses are generated, energy istransferred from capacitor C1 to C2, and has to be transferred back toC1 by the power supply before the subsequent pulse in repetitive TMS(rTMS) operation. However, if a biphasic magnetic pulse is used toproduce a predominantly unipolar electric field pulse, as shown in FIG.5 and FIG. 12A-C, energy is transferred from C2 to C1 and then back fromC1 to C2 during the pulse. Thus, there is no need for rebalancing alarge amount of energy between the capacitors before the subsequentpulse, except for “topping off” the capacitors to compensate for theenergy dissipated in losses during the pulse, as is the case inconventional biphasic TMS systems. With both monophasic and biphasiccTMS magnetic field pulses, the energy returning from the coil aftereach pulse is recycled, unlike that in conventional monophasicconverters, which is dissipated in a resistor. However, compared to cTMSbiphasic magnetic field pulses, monophasic magnetic field pulses requirehigher power capability of the cTMS power supply circuit that movescharge between the two capacitors.

Thus, the cTMS system is particularly well suited to generatehigh-frequency trains of predominantly unipolar electric field pulses.Using the results in FIG. 11, the unipolar rTMS power dissipation andcoil heating of cTMS can be compared to that of conventional monophasicstimulators. The cTMS² configuration is 5-6 times more efficient and hasabout three times less coil heating than the Magstim 200 and MagPro X100while producing the same neuronal depolarization and comparablehyperpolarization/depolarization ratio. For a pulse train frequency of10 Hz, the Magstim 200, MagPro X100, and cTMS² pulse configurationsdescribed in FIG. 11 dissipate 1600, 1420, and 260 W, respectively,while the coil dissipation, assuming coil resistance of 10 mΩ, is 248,222, and 80 W, respectively. If an iron-core coil is used, cTMS energydissipation and coil heating can be further reduced to about 65 and 20W, respectively. Therefore, with its substantially lower powerdissipation and coil heating, the cTMS system can enable rTMS withpredominantly unipolar electric field pulses. Recent research hasindicated that rTMS with predominantly unipolar electric field pulsesmay have a stronger modulating effect on brain function, and, therefore,could be a more effective therapeutic intervention.

Referring to FIGS. 13A and 13B, in an alternative embodiment,illustrative block diagrams of power electronics and a control computersystem 102 a for a controllable pulse parameter transcranial magneticstimulation (cTMS) system are shown. The cTMS system includes a cTMScircuit 1320 for driving a stimulating coil L. The cTMS circuit 1320includes energy storage capacitor (or bank of capacitors) C1,controllable semiconductor switch Q1, a gate drive 1302, charger 1310,capacitor discharger 1322, diode D1, and resistor R1. The cTMS systemfurther includes a digital data processing device, such as controlcomputer system 102 a, which includes a controller board 1305.

This particular embodiment enables adjustment of the amplitude and thepulse width of the induced electric field over a continuous range ofvalues, and the induced electric field pulses have an approximatelyrectangular shape. The semiconductor switch Q1 is implemented with anIGBT, which unlike an SCR, can be turned off from a gate terminal 1304.Further, the diode D1 and the energy dissipation resistor R1 areconnected across the TMS coil L, to provide a discharge path for thecoil current when Q1 is turned off. The energy storage capacitor C1 islarger than those used in conventional TMS stimulators to provide awider range of pulse width control and approximately rectangular inducedelectric field pulses.

Similar to the cTMS circuit described in connection with FIGS. 2A, 2B,and 3A, the cTMS circuit 1320 shown in FIG. 13A is controlled by thecontroller board 1305 shown in FIG. 13B, which resides in the controlcomputer 102 a. Through the controller board 1305, the operatorspecifies the voltage of capacitor C1, which determines the amplitude ofthe induced electric field. The operator also specifies the on time andthe off time of switch Q1, which determine the pulse timing and thepulse width (PW⁺).

Referring to FIG. 14, in another embodiment, a schematic diagram of thecTMS circuit is shown. Stray inductance in the critical high-currentpaths of the circuit can cause power loss and voltage spikes duringturn-off of switch Q1, which can cause component damage, as previouslydiscussed. Therefore, the wiring and component locations in the cTMScircuit are arranged to reduce and/or minimize the stray inductance.However, stray inductances cannot be completely eliminated. Therefore,the cTMS circuit includes a number of snubber components. The snubbercomponents assist the coil current commutation between the switch Q1 andthe diode D1 and inhibits and/or prevents voltage overshoots and energydissipation in the semiconductor switch Q1. A snubber capacitor orcombination of capacitors C5 is mounted between the collector terminalof switch Q1 and the anode terminal of diode D1 to prevent the collectorvoltage from spiking during switch Q1 turn-off as a result of parasiticinductance of the capacitor bank C1 and the connecting wires. Acapacitor C3 is mounted between the collector and emitter terminals ofthe switch Q1 to suppress high-voltage spikes across the terminals ofswitch Q1. A snubber circuit 1402, which includes diode D2, capacitorC4, and resistor R2, transiently absorbs the current flowing through thecoil L when Q1 is turned off. This supports the current commutation todiode D1 and resistor R1, as previously discussed.

The energy storage bank of capacitors C1 comprises six 118 μF. (averagemeasured value) oil-filled pulse capacitors. The bank of capacitors C1is charged by a Magstim Booster Module Plus (The Magstim Co., Whitland,UK) and a Magstim capacitor voltage control circuit. The semiconductorswitch Q1 is a 4500 Volt/600 Amp (direct current rating) IGBT modulefrom Powerex, Inc. (Youngwood, Pa.). The IGBT (switch Q1) is controlledwith a high-voltage optically-isolated gate drive 1302 by Applied PowerSystems, Inc. (Hicksville, N.Y.). The controller board 1305 sendstriggering pulses to the gate drive 1302. As previously described, thepulse width is set by the operator. The diode D1 is implemented with twoseries-connected, fast 1800 Volt/102 Amp (direct current rating) diodesby Semikron GmbH (Nuremberg, Germany). The snubber capacitors C3-C5 arehigh-voltage, high-current polypropylene film and paper film/foilcapacitors. The snubber diode D2 includes three series-connectedfast-recovery 1200 Volt/60 Amp (direct current rating) diodes fromInternational Rectifier (El Segundo, Calif.). The stimulating coil L isa custom-made Magstim 5.5 cm mean diameter round coil with an inductanceof 16 μH.

The cTMS circuit of FIG. 14 was tested with capacitor voltages of up to1650 Volts, and peak coil currents of up to 7 kA. The peak intensity(i.e. amplitude of the electric field) of the cTMS system is equal tothat of commercial Magstim Rapid stimulators. Unlike conventionalstimulators, however, the cTMS system of the disclosed subject matterallows pulse width control with a range between 5 μs and 160 μs.

The electric field induced by the cTMS system was estimated with asingle-turn 5 cm diameter search coil placed two centimeters from theface of the cTMS coil L. The search coil was connected to a digitizingoscilloscope as well as to a first-order low-pass filter with 150 μstime constant, which outputs a scaled estimate of the neuronal membranevoltage waveform.

Referring to FIGS. 15A-C, illustrative waveforms of measured capacitorC5 voltage (FIG. 15A), search coil voltage V_(S) (proportional to theinduced electric field, FIG. 15B), and the estimated shape of theneuronal membrane voltage (VF) (FIG. 15C), which is determined byfiltering the search coil voltage V_(S) through a low-pass filter, areshown. The waveforms show six different pulse widths (i.e., 20, 40, 60,80, 100, and 120 μs). It can be seen in FIG. 15B that the inducedpulses, which are proportional to the electric field, have approximatelyrectangular shape, especially for brief pulses (e.g., 20 μs pulse).

As expected, overshoot and high-frequency ringing are present on thecapacitor C5 voltage (FIG. 15A) and search coil voltage (proportional tothe electric field, FIG. 15B) during switch Q1 turn-off, due to strayinductance. However, these transients are suppressed to a safe level bythe snubber circuits. In particular, the capacitor voltage overshootdoes not exceed 7% of the initial capacitor voltage, and the voltageacross the switch Q1 never exceeds approximately twice the initialcapacitor voltage, and is thus well below the 4,500 V rating of the IGBT(Q1). These results indicate the feasibility of high coil currentcommutation through appropriate choice of semiconductor switches, switchgating, snubber design, and minimization of stray inductance.

The above described cTMS implementation can be used to compare theintrinsic efficiency of rectangular unipolar electric field pulsesversus conventional unipolar cosine pulses. In order to emulateconventional monophasic magnetic field pulses, the cTMS implementationwas reconfigured to use a smaller capacitor and switch Q1 was kept onuntil the coil current decayed to zero. The comparison of rectangularpulses used the same initial capacitor voltage, and the cTMS pulse widthwas adjusted to achieve the same estimated neuronal depolarization. Theenergy dissipation per pulse was calculated using the formula:

${{\Delta\; W_{C}} = {( {{1/2}{\sum\limits_{\substack{{sum}\mspace{14mu}{of}\mspace{14mu}{all} \\ {capacitors} \\ {before}\mspace{14mu}{pulse}}}{{Ci}( V_{Ci} )}^{2}}} ) - ( {{1/2}{\sum\limits_{\substack{{sum}\mspace{14mu}{of}\mspace{14mu}{all} \\ {capacitors} \\ {after}\mspace{14mu}{pulse}}}{{Ci}( V_{Ci} )}^{2}}} )}},$where Ci refers to all capacitors in the stimulator power electronics,and where capacitor Ci has voltage V_(Ci).

Compared to conventional monophasic magnetic field pulses with risetimes of 72 and 101 μs, the corresponding rectangular pulses dissipated20 and 28% less energy, respectively. The cTMS circuit of FIG. 14 doesnot recycle pulse energy (pulse energy is dissipated in resistor R1 inFIG. 14), so this gain in efficiency comes solely from the rectangularpulse shape. With energy recycling, which is implemented in the circuitin FIG. 2 and FIG. 3, efficiency will be even higher, as discussedabove.

The cTMS system disclosed herein enables an operator to adjust variouspulse shape parameters (previously described in detail) of an electricfield pulse induced in the brain of a patient. The values of these pulseshape parameters can be chosen based on which medical application isbeing implemented and/or a patient's physiological characteristics.Further, the capability to control pulse parameters enables a medicalprofessional to study the contribution of pulse characteristics toobserved physiological effects of an induced electric field pulse.

Additionally, the cTMS systems disclosed herein (see FIGS. 2 and 3)produce approximately rectangular induced electric field pulses, whichare more energy efficient for neuronal stimulation than sinusoidalpulses produced by existing TMS systems, as previously described.Moreover, the cTMS systems depicted in FIGS. 2 and 3 also enable anoperator to vary the degree of bidirectionality of the induced pulseover a continuous range from a predominantly unipolar to a bipolarelectric field pulse.

In view of the effects of the TMS pulse characteristics on physiologicalresponses, and the capability of cTMS systems disclosed herein tocontrol the pulse parameters, the cTMS systems disclosed herein have thepotential for enabling diverse clinical and research applications. Forexample, the cTMS systems can be used to determine strength-durationcurves (i.e., the induced electric field pulse amplitude vs. the pulsewidth that produces threshold neuronal stimulation). Strength-durationcurves can be used to estimate a neuronal membrane time constant, andcan therefore be a useful tool for diagnosing and studying neurologicaldisease. Strength-duration curves can also be used to optimizestimulation paradigms for different cortical regions, and activateselectively different neuronal types possessing different membrane timeconstants and responsivity to pulse shape characteristics. Thus, thecapability to adjust the pulse shape in the cTMS system could enableoptimization of the stimulus parameters for various applications.

TMS with briefer, high-amplitude pulses requires less energy deliveredto the stimulating coil, thereby increasing efficiency and decreasingheating. Thus, TMS and rTMS with brief (e.g., 20-50 μs) rectangularpulses are more energy efficient.

Recent studies indicate that rTMS with predominately unipolar inducedelectric fields can yield more potent modulation of neuronalexcitability compared to standard bidirectional rTMS.

See for example: M. Sommer, N. Lang, F. Tergau, and W. Paulus, “Neuronaltissue polarization induced by repetitive transcranial magneticstimulation” Neuroreport, vol. 13, no. 6, pp. 809-11, 2002; A. Antal, T.Z. Kincses, M. A. Nitsche, O. Bartfai, I. Demmer, M. Sommer, and W.Paulus, “Pulse configuration-dependent effects of repetitivetranscranial magnetic stimulation on visual perception,” Neuroreport,vol. 13, no. 17, pp. 2229-33, 2002; T. Tings, N. Lang, F. Tergau, W.Paulus, and M. Sommer, “Orientation-specific fast rTMS maximizescorticospinal inhibition and facilitation,” Exp Brain Res, vol. 164, no.3, pp. 323-33, 2005; N. Arai, S. Okabe, T. Furubayashi, Y. Terao, K.Yuasa, and Y. Ugawa, “Comparison between short train, monophasic andbiphasic repetitive transcranial magnetic stimulation (rTMS) of thehuman motor cortex,” Clin Neurophysiol, vol. 116, no. 3, pp. 605-13,2005; and J. L. Taylor and C. K. Loo, “Stimulus waveform influences theefficacy of repetitive transcranial magnetic stimulation,” J AffectDisord, vol. 97, pp. 271-276, 2007.

The cTMS system circuit (see FIGS. 2 and 3) is intrinsically energyefficient since the coil transfers charge between two energy-storagecapacitors, rather than dissipating it in a resistor, like theconventional monophasic TMS topology does. Further, the cTMS system (seeFIGS. 2 and 3) can induce predominately unipolar electric fields withbiphasic magnetic pulses having fast rise time and slow fall times,which require substantially less energy delivered to the coil. Thus,such cTMS enables high-frequency unidirectional rTMS, yieldingpotentially stronger neuromodulation effects that can be used fortherapeutic purposes in neurological and psychiatric illness.

Variations, modifications, and other implementations of what isdescribed herein may occur to those of ordinary skill in the art withoutdeparting from the spirit and scope of the disclosed subject matter.Further, the various features of the embodiments described herein alsocan be combined, rearranged, or separated without departing from thespirit and scope of the disclosed subject matter as defined by thefollowing claims.

I claim:
 1. A magnetic stimulation system for inducing approximatelyrectangular electric field pulses in a body organ, comprising: anelectrical energy storage device comprising a first capacitor and asecond capacitor coupled to charging means for being respectivelycharged positively and negatively by said charging means to respectiveoperator-controlled voltages; a stimulating coil; and a switching meansfor electrically coupling said electrical energy storage device to saidstimulating coil to produce current pulses in said stimulating coilwhich generates, in response to the current pulses, magnetic fieldpulses that can induce approximately rectangular electric field pulsesin the body organ, wherein said switching means comprises a firstsemiconductor switch and a second semiconductor switch, the first andsecond capacitors being alternatingly electrically coupled to saidstimulating coil by said first and second semiconductor switches,respectively.
 2. The system of claim 1, wherein the magnetic fieldpulses induce positive and negative electric field pulses in the bodyorgan, with at least the positive electric field pulses comprising theapproximately rectangular electric field pulses.
 3. The system of claim2, wherein the induced positive and negative electric field pulses arebipolar pulses.
 4. The system of claim 1, further comprising anoperator-controlled apparatus that includes means for selectivelyadjusting a pulse width of the induced electric field pulses.
 5. Thesystem of claim 1, wherein the magnetic field pulses induce positive andnegative electric field pulses in the body organ, and wherein the systemfurther comprises an operator-controlled apparatus that includes meansfor selectively adjusting a degree of bidirectionality of the inducedpositive and negative electric field pulses.
 6. A system for inducingapproximately rectangular electric field pulses in a body organ,comprising: an electrical energy storage device; a stimulating coil; aswitching device electrically coupling said electrical energy storagedevice to said stimulating coil and configured to produce current pulsesin said stimulating coil and, in response to said current pulses,magnetic field pulses capable of inducing electric field pulses in thebody organ; and a user-controlled device configured to selectivelyadjust over a continuous range of values a plurality of parameters ofthe induced electric field pulses in the body organ and configured toindependently control the parameters of the electric field pulsesinduced in the body organ; wherein the electrical energy storage deviceincludes a first electrical energy storage device and a secondelectrical energy storage device, and the switching device includes afirst switching device and a second switching device, the first andsecond energy storage devices being alternatingly electrically coupledto said coil by respective said first and second switching devices. 7.The system of claim 6, wherein the parameters include pulse amplitude,pulse width, pulse repetition frequency, and degree of bidirectionality.8. The system of claim 7, wherein the user-controlled device isconfigured to independently control at least two of the parameters. 9.The system of claim 6, wherein the first and second switching devicesare adapted to switch between an ON state and an OFF state in responseto timing pulses generated by the user-controlled device.
 10. The systemof claim 9, wherein the user-controlled device is configured toselectively adjust the width of the electrical field pulses induced inthe body organ by independently adjusting a time interval in which thefirst switching device is in an ON state, and a time interval in whichthe second switching device is in an ON state.
 11. The system of claim10, wherein adjusting the width of the electrical field pulses inducedin the body organ further includes adjusting a first and second phase ofthe induced electric field pulses independently of each other, the firstand second phases having opposite polarity.
 12. The system of claim 10,wherein the user-controlled device is configured to control the width ofthe electrical field pulses induced in the body organ by independentlycontrolling the timing pulses sent to the first and second switchingdevices.
 13. The system of claim 7, wherein the user-controlled deviceis configured to selectively adjust the degree of bidirectionality ofthe electrical field pulses induced in the body organ by adjusting aratio of the voltage supplied to the first energy storage device and thevoltage supplied to the second energy storage device.
 14. The system ofclaim 13, wherein the user-controlled device is configured to controlthe degree of bidirectionality of the electrical field pulse induced inthe body organ by independently selecting the voltage supplied to thefirst energy storage device and the voltage supplied to the secondenergy storage device.
 15. The system of claim 14, wherein the first andsecond energy storage devices are capacitors.
 16. The system of claim15, wherein the system further comprises a charging device to charge thefirst capacitor to an independently selectable positive voltage and tocharge the second capacitor to an independently selectable negativevoltage, wherein the user-controlled device is configured toindependently select the positive and negative voltages.
 17. The systemof claim 16, wherein the user-controlled device is configured the adjustthe bidirectionality the electric field pulses so that the field pulsesinduced in the body organ can be varied from bipolar pulses tosubstantially unipolar pulses.
 18. The system of claim 6, furthercomprising a detecting device to detect physiological effects induced inthe body organ by the electric field pulses.
 19. The system of claim 18,wherein the user-controlled device is configured to adjust and controlthe parameters based on the detected physiological effects in the bodyorgan.
 20. The system of claim 19, wherein the physiological effectdetected is a voltage change on the neuronal membrane of the body organ.21. The system of claim 6, wherein the first and second switchingdevices are semiconductor switching devices, each comprising one of aninsulated gate bipolar transistor and a gate turn-off thyristor.
 22. Asystem for inducing approximately rectangular electric field pulses in abody organ, comprising: a first electrical energy storage deviceconfigured to be charged to an independently selectable positivevoltage; a second electrical storage device configured to be charged toan independently selectable negative voltage; a stimulating coil; aswitching device electrically coupling said first energy storage devicefor a first period of time to produce current pulses with a positiverate of change in the stimulating coil and electrically coupling saidsecond electrical energy storage device for a second period of time tosaid stimulating coil to produce current pulses with a negative rate ofchange in the stimulating coil, and configured to produce, in responseto said current pulses, magnetic field pulses capable of inducingapproximately rectangular electric field pulses in the body organ; and auser-controlled device configured to selectively adjust over acontinuous range of values a plurality of parameters of the inducedelectric field pulses in the body organ and configured to independentlycontrol the parameters of the electric field pulses induced in the bodyorgan, wherein the user-controlled device is further configured toindependently select said positive and negative voltages, and whereinthe voltages on the energy storage devices are not reversed during apulse.
 23. The system of claim 22, wherein the parameters include pulseamplitude, pulse width, pulse repetition frequency, and degree ofbidirectionality.
 24. The system of claim 23, wherein theuser-controlled device is configured to independently control at leasttwo of the parameters.
 25. The system of claim 23, wherein the first andsecond electrical energy storage devices include capacitors and theswitching device includes a first switching device and a secondswitching device, the first and second capacitors being alternatinglyelectrically coupled to said coil by said respective first and secondswitching devices.
 26. The system of claim 25, wherein the first andsecond switching devices are adapted to switch between an ON state andan OFF state in response to timing pulses generated by theuser-controlled device.
 27. The system of claim 26, wherein theuser-controlled device is configured to selectively adjust the width ofthe electrical field pulses induced in the body organ by independentlyadjusting a time interval in which the first switching device is in anON state, and a time interval in which the second switching device is inan ON state.
 28. The system of claim 27, wherein the user-controlleddevice is further configured to adjust a first phase and a second phaseof the induced electric field pulses independently of each other, thefirst and second phases having opposite polarity.
 29. The system ofclaim 27, wherein the user-controlled device is configured to controlthe width of the electrical field pulses induced in the body organ byindependently controlling the timing pulses sent to the first and secondswitching devices.
 30. The system of claim 29, wherein theuser-controlled device is configured to selectively adjust the degree ofbidirectionality of the electrical field pulses induced in the bodyorgan by adjusting a ratio of the voltage supplied to the first energystorage member and the voltage supplied to the second energy storagemember.
 31. The system of claim 30, wherein the user-controlled deviceis configured to control the degree of bidirectionality of theelectrical field pulse induced in the body organ by independentlyselecting the voltage supplied to the first energy storage member andthe voltage supplied to the second energy storage member.
 32. The systemof claim 31, wherein the system further comprises a charging device tocharge the first capacitor to an independently selectable positivevoltage and to charge the second capacitor to an independentlyselectable negative voltage, wherein the user-controlled device isconfigured to independently select the positive and negative voltages.33. The system of claim 32, wherein by adjusting the bidirectionalitythe electric field pulses, the field pulses induced in the body organcan be varied from bipolar pulses to substantially unipolar pulses. 34.The system of claim 22, further comprising a detecting device to detectphysiological effects induced in the body organ by the electric fieldpulses.
 35. The system of claim 34, wherein the user-controlled deviceis configured to adjust and control the parameters based on the detectedphysiological effects in the body organ.
 36. The system of claim 35,wherein the physiological effect detected is a voltage change on theneuronal membrane of the body organ.
 37. The system of claim 36, whereinthe first and second switching devices are semiconductor switchingdevices, each comprising one of an insulated gate bipolar transistor anda gate turn-off thyristor.
 38. A magnetic stimulation system forinducing approximately rectangular electric field pulses in a bodyorgan, comprising: a first electrical energy storage device configuredto be charged to an independently selectable positive voltage; a secondelectrical storage device configured to be charged to an independentlyselectable negative voltage; a stimulating coil; a switching deviceelectrically coupling said first energy storage device for a firstperiod of time to produce current pulses with a positive rate of changein the stimulating coil and electrically coupling said second electricalenergy storage device for a second period of time to said stimulatingcoil to produce current pulses with a negative rate of change in thestimulating coil, and configured to produce, in response to said currentpulses, magnetic field pulses capable of inducing approximatelyrectangular electric field pulses in the body organ; and a protectingdevice electrically connected to the simulation coil to controlpotential voltage overshoots in the system, wherein, the first andsecond electrical energy storage devices and the switching device arepositioned relative to each other and are interconnected in such a wayas to minimize stray inductance in the system.
 39. The system of claim38, wherein the protecting device is a snubber circuit.
 40. The systemof claim 39, wherein the snubber circuit is electrically connected inparallel with the first and second energy storage devices.
 41. Thesystem of claim 38, further comprising a user-controlled deviceconfigured to selectively adjust over a continuous range of values aplurality of parameters of the induced electric field pulses in the bodyorgan and configured to independently control the parameters of theelectric field pulses induced in the body organ.
 42. The system of claim41, wherein the user-controlled device is further configured toindependently select said positive and negative voltages.
 43. The systemof claim 41, wherein the parameters include pulse amplitude, pulsewidth, pulse repetition frequency, and degree of bidirectionality. 44.The system of claim 43, wherein the first and second switching devicesare adapted to switch between an ON state and an OFF state in responseto timing pulses generated by the user-controlled device and theuser-controlled device is configured to selectively adjust the width ofthe electrical field pulses induced in the body organ by independentlyadjusting a time interval in which the first switching device is in anON state, and a time interval in which the second switching device is inan ON state.
 45. The system of claim 44, wherein the user-controlleddevice is further configured to adjust a first and second phase of theinduced electric field pulses independently of each other, the first andsecond phases having opposite polarity.
 46. The system of claim 44,wherein the user-controlled device is configured to control the width ofthe electrical field pulses induced in the body organ by independentlycontrolling the timing pulses sent to the first and second switchingdevices.
 47. The system of claim 43, wherein the user-controlled deviceis configured to selectively adjust the degree of bidirectionality ofthe electrical field pulses induced in the body organ by adjusting aratio of the voltage supplied to the first energy storage device and thevoltage supplied to the second energy storage device, and theuser-controlled device is configured to control the degree ofbidirectionality of the electrical field pulse induced in the body organby independently selecting the voltage supplied to the first energystorage device and the voltage supplied to the second energy storagedevice.